Gonçalves et al. Orphanet Journal of Rare Diseases 2015, 10(Suppl 1):P5
http://www.ojrd.com/content/10/S1/P5
POSTER PRESENTATION
Open Access
Tissue remodeling after RNAi-mediated
knockdown of TTR in a Familial Amyloidotic
Polyneuropathy mouse model
Nádia Pereira Gonçalves1*, Paula Gonçalves1, Miguel Ventosa2, Ana Varela Coelho2, Maria João Saraiva1
From First European Congress on Hereditary ATTR amyloidosis
Paris, France. 2-3 November 2015
Background
Transthyretin (TTR) deposition in the peripheral nervous
system (PNS) is the hallmark of Familial Amyloidotic
Polyneuropathy (FAP). Mice expressing human TTR
with the V30M mutation in a heterozygous heat shock
factor 1 (Hsf-1) background show extensive TTR deposits in PNS and gastrointestinal tract, as well as extracellular matrix (ECM) remodeling, similar to those seen in
human FAP patients. Currently, liver transplantation is
the only available treatment to halt the progression of
clinical symptoms in FAP. Due to the limitations of this
procedure, it is of utmost importance to develop alternative therapeutic strategies. In this regard, an RNAi therapeutic targeting TTR for the treatment of FAP is
currently in Phase 3 clinical development. An ongoing
phase 2 clinical trial in FAP patients demonstrated promising results as a mean plasma TTR reduction of 80%,
sustained for over nine months, led to a decrease in neuropathy progression compared to historical data.
Methods
To dissect molecular changes occurring in tissues upon
RNAi-mediated knockdown of TTR, we treated both
chronically and acutely the Hsf/V30M FAP mouse model,
in different stages of TTR deposition and analyzed histopathological and biochemical changes in the most affected
organs.
tract. In addition, this treatment resulted in ECM remodeling with decreased levels of matrix metalloproteinase-2 (MMP-2) expression and MMP-9 activity in
dorsal root ganglia. Importantly, MMP-2 protein levels
were found down regulated in plasma samples from
older mice treated with RNAi while animals treated
with Tafamidis, Anakinra or Doxycycline/TUDCA
showed no difference, suggesting that ECM remodeling
with decreased MMP-2 might be a specific effect of
RNAi.
Conclusion
Collectively, our data show that silencing TTR liver
synthesis in vivo can modulate TTR-induced pathology
in the PNS.
Authors’ details
1
Instituto de Inovação e Investigação em Saúde (I3S), Instituto de Biologia
Molecular e Celular (IBMC), Universidade do Porto, Molecular Neurobiology
Unit, 4150-180, Porto, Portugal. 2Instituto de Tecnologia Química e Biológica
António Xavier (ITQB), Universidade Nova de Lisboa, Mass Spectrometry,
2781-901, Oeiras, Portugal.
Published: 2 November 2015
doi:10.1186/1750-1172-10-S1-P5
Cite this article as: Gonçalves et al.: Tissue remodeling after RNAimediated knockdown of TTR in a Familial Amyloidotic Polyneuropathy
mouse model. Orphanet Journal of Rare Diseases 2015 10(Suppl 1):P5.
Results
Our data show that inhibition of TTR expression by the
liver prevent and reverse TTR deposition in PNS and GI
1
Instituto de Inovação e Investigação em Saúde (I3S), Instituto de Biologia
Molecular e Celular (IBMC), Universidade do Porto, Molecular Neurobiology
Unit, 4150-180, Porto, Portugal
Full list of author information is available at the end of the article
© 2015 Gonçalves et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.